Many blood-ingesting pests are known to feed on humans and animals. These pests are vectors for pathogenic microorganisms which threaten human and animal health, including commercially important livestock, pets and other animals. Mosquitoes, a blood-ingesting pest, transmit diseases caused by viruses, and many are vectors for disease-causing nematodes and protozoa, including malaria, filariasis, dengue, yellow fever and encephalitis. The World Health Organization (WHO) estimates that more than 300 million clinical cases each year are attributable to mosquito-borne illnesses. Despite great strides over the last 50 years, mosquito-borne illnesses continue to pose significant risks to the population.
The transmission of mosquito-borne diseases is dependent on a threshold density of competent vector mosquitoes and a reservoir of infected hosts. In the case of Dengue virus, the fastest growing mosquito-borne disease globally in terms of infected humans/yr (˜250 million), competent vectors are several species of Aedes mosquitoes, most importantly, the species Aedes aegypti. Malaria, which is still is a serious threat in many parts of the world, is mainly transmitted by the Anopheles mosquitoes, the most important vectors being Anopheles dirus, Anopheles minimus, Anopheles philippinensis, and Anopheles sundaicus. The spread of mosquito-borne diseases can be restricted by decreasing mosquito populations in areas of high pathogen transmission.
Various pesticides have been employed in efforts to control or eradicate populations of disease-bearing blood-ingesting pests. To date, only four classes of pesticides, which share two modes of action, are approved by the World Health Organization (WHO) for eradicating mosquitoes. One class of pesticide is chlorinated hydrocarbons, for example dichlorodiphenyltrichloroethane (DDT). DDT has been used in attempts to eradicate malaria-bearing mosquitoes throughout the world. Other examples of chlorinated hydrocarbons are benzene hexachloride, lindane, chlorobenzilate, methoxychlor, and the cyclodienes (e.g., aldrin, dieldrin, chlordane, heptachlor, and endrin). The long-term stability of many of these pesticides and their tendency to bioaccumulate render them particularly dangerous to many non-pest organisms.
The pyrethroids, another class of pesticides, include products such as permethrin (Biomist®), resmethrin (Scourge®) and sumithrin (Anvil®). Although pyrethroids are derived from plants, inhalation of these pesticides are known to cause adverse side effects, such as coughing, wheezing, shortness of breath, runny or stuffy nose, chest pain, or difficulty breathing and skin contact may lead to rash, itching, or blisters. The long term effects due to pyrethroid exposure include disruption of the endocrine system in human males; the estrogenizing effects of pyrethroids can cause lowered sperm counts. Long term exposure can also lead to the abnormal growth of breast tissue, development of breasts in males and cancerous breast tissue in both male and females. Pyrethroids also pose neurotoxic effects and are known carcinogens.
Another class of pesticides is the organophosphates, which is perhaps the largest and most versatile class of pesticides. Organophosphates include, for example, parathion, Malathion™, diazinon, naled, methyl parathion, and dichlorvos. Organophosphates are generally much more toxic than the chlorinated hydrocarbons. Their pesticidal effect results from their ability to inhibit the enzyme cholinesterase, an essential enzyme in the functioning of the insect nervous system. However, they also have toxic effects on many animals, including humans.
The carbamates, a relatively new group of pesticides, include such compounds as carbamyl, methomyl, and carbofuran. These compounds are rapidly detoxified and eliminated from animal tissues. Their toxicity is thought to involve a mechanism similar to the mechanism of the organophosphates; consequently, they exhibit similar shortcomings, including animal toxicity.
In addition to the adverse side effects due to insecticide exposure discussed above, blood-ingesting pests can develop resistances to these classes of compounds. A mutation at a single target site can result in mosquito resistance to DDT and pyrethroids or to organophosphates and carbamates. Species of Anopheles mosquitoes, for example, have been known to develop resistance to DDT and dieldrin. DDT substitutes, such as Malathion™, propoxur and fenitrothion are available; however, the cost of these substitutes is much greater than the cost of DDT. Mosquitoes can also express multiple insecticide-resistance mechanisms (Perera M D B, et al.; Malar J. 2008; 7:168). For example, in several populations of the major malaria vector in Africa, Anopheles gambiae mosquitoes, mutations in the DDT/pyrethroid target site, known as knockdown resistance (kdr) alleles, have been found in conjunction with resistance alleles of the acetylcholinesterase gene (Ace-1R), the target site of organophosphates and carbamates (Yewhalaw, et al.; PLoS ONE. 2011; 6:e16066.).
There is a longstanding need for pesticidal compounds that are pest-specific, that reduce or eliminate direct and/or indirect threats to human health posed by presently available pesticides, that are environmentally compatible, are not toxic to non-pest organisms, and have reduced or no tendency to bioaccumulate.
In mosquitoes, the conversion of protein from a blood meal into yolk proteins and lipids for the developing oocytes is an essential part of the reproductive cycle. Blood feeding by a female Aedes aegypti mosquito initiates a series of events in the midgut, the fat body and the ovaries. Female mosquitoes ingest more than their own weight in blood in a short time and then spend the next 36 hours converting the amino acids from the blood proteins into the constituents of their eggs, a process termed vitellogenesis. The process begins in the midgut with the digestions of blood meal proteins and the regulation of digestive enzyme synthesis in the midgut occurs in two phases. The early phase begins immediately after ingestion of the meal and involves activation of translation. The synthesis of early trypsin serves as a model for this phase. The late phase begins 6-8 hours after the meal and involves activation of transcription. The synthesis of late trypsin serves as a model for this phase.
It is believed that this regulatory mechanism is not restricted to mosquitoes considering that the evolutionarily-related sandfly, which is the insect vector for Leishmania parasites, has a very similar blood feeding mechanism.
Blood meal feeding in pests creates a unique metabolic challenge as a result of the extremely high protein and iron content of blood.
It is therefore an object of the invention to provide improved compounds to control or eradicate populations of blood feeding pests, such as mosquitoes.
It is a further object of the invention to provide improved compounds that are lethal to blood feeding pests, such as blood-feeding mosquitoes.
It is a further object of the invention to provide improved compounds that prevent or reduce the spread of illnesses by blood-feeding pests.
It is a further object of the invention to provide improved methods for control the reproduction of or eradicate blood feeding pests, such as mosquitoes.
It is a further object of the invention to provide improved methods for preventing or reducing the spread of illnesses by blood feeding pests, such as mosquitoes.